Novel Approaches to Maintaining Organ Function in Sepsis

维持脓毒症器官功能的新方法

• 批准号: 10153818
• 负责人: PING WANG
• 金额: $ 51.18万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153818
• 关键词: Address; Affect; American; Animals; Antisepsis; Attenuated; Biological Response Modifier Therapy; Blood Circulation; Blood Vessels; Cause of Death; Cell Communication; Cells; Development; Endothelial Cells; Epidermal Growth Factor; Extravasation; Germ; Grant; Half-Life; Health Expenditures; Human; Inflammation; Inflammatory Response; Injections; Injury; Leukocytes; Lung; Malignant Neoplasms; Molecular; Morbidity - disease rate; Mus; Neutrophil Activation; Neutrophil Infiltration; Oligopeptides; Organ; Patients; Pattern; Peptides; Pharmaceutical Preparations; Proteins; RNA-Binding Proteins; Recombinants; Regulation; Research; Research Support; Sepsis; Septic Shock; Therapeutic; Therapeutic Agents; Toxic effect; Vascular Endothelial Cell; base; cost; design; effective therapy; improved; innovation; milk fat globule; mortality; neutralizing antibody; neutrophil; novel strategies; novel therapeutics; organ injury; prevent; programs; public health relevance; septic; septic patients; small molecule; trafficking

 DESCRIPTION (provided by applicant): In the US, sepsis affects more than 750,000 people annually, with a mortality rate as high as 30%. There is still no effective therapy for patients wih sepsis and septic shock. Excessive neutrophil infiltration is a major determinant of organ injury in sepsis, suggesting that targeting neutrophil trafficking is a rational strategy to reduce sepsis morbidity and mortality. The interaction between neutrophils and activated endothelial cells (ECs) is a key regulator of neutrophil infiltration. We have discovered that milk fat globule-epidermal growth factor-factor 8 (MFG-E8) is able to reduce the number of neutrophils in organs of septic animals. Administration of recombinant human MFG-E8 after sepsis not only attenuated organ damage, but also doubled the survival of septic animals. We have also discovered that cold-inducible RNA-binding protein (CIRP) is released into the circulation in sepsis and functions as a damage-associated molecular pattern (DAMP). We have demonstrated that blocking CIRP activities with CIRP-neutralizing antibodies after sepsis not only inhibited inflammation, but also markedly improved the survival of septic animals. Recently, we have demonstrated that injection of recombinant murine CIRP into healthy mice caused EC activation and vascular leakage in the lungs. One focus of this proposal is to further elucidate the mechanisms responsible for MFG-E8's regulation of neutrophil trafficking and CIRP's control of EC activation. These findings will guide the design and development of new therapeutics for treating sepsis. Due to the complexity and difficulty in developing protein-based biotherapeutics, we focused on identifying small molecule-like oligopeptides derived from MFG-E8 and CIRP. To date, we have identified two candidate peptides, MSP68 and C23, derived from MFG-E8 and CIRP, respectively. We will further evaluate their efficacy, half-life and toxicity for treating sepsis. In this research program, we will address the following three key questions: 1) How does MFG-E8 inhibit neutrophil activation and infiltration in sepsis? 2) How does CIRP cause vascular EC activation and injury in sepsis? 3) Can we develop an anti-sepsis strategy targeting the neutrophil-EC interaction? The proposed research will lead to a new direction for the development of innovative therapeutics to treat patients suffering from sepsis and septic shock.

 描述（由申请人提供）：在美国，败血症每年影响超过75万人，死亡率高达30%。对于脓毒症和感染性休克患者，目前仍缺乏有效的治疗方法。过度的中性粒细胞浸润是脓毒症器官损伤的主要决定因素，提示靶向中性粒细胞运输是减少脓毒症的合理策略 发病率和死亡率。中性粒细胞和活化的内皮细胞（EC）之间的相互作用是中性粒细胞浸润的关键调节因子。我们已经发现乳脂球表皮生长因子8（MFG-E8）能够减少脓毒症动物器官中的中性粒细胞数量。脓毒症后给予重组人MFG-E8不仅减轻了器官损伤，而且使脓毒症动物的存活率增加了一倍。我们还发现冷诱导RNA结合蛋白（CIRP）在脓毒症中释放到循环中，并作为损伤相关分子模式（DAMP）发挥作用。我们已经证明，在脓毒症后用CIRP中和抗体阻断CIRP活性不仅抑制炎症，而且显著改善脓毒症动物的存活率。最近，我们已经证明，注射重组鼠CIRP到健康小鼠引起EC激活和肺血管渗漏。该提议的一个焦点是进一步阐明负责MFG-E8调节中性粒细胞运输和CIRP控制EC活化的机制。这些发现将指导设计和开发治疗脓毒症的新疗法。由于开发基于蛋白质的生物治疗药物的复杂性和困难性，我们专注于鉴定来自MFG-E8和CIRP的小分子样寡肽。迄今为止，我们已经鉴定了两种候选肽，MSP 68和C23，分别来源于MFG-E8和CIRP。我们将进一步评估其治疗脓毒症的疗效、半衰期和毒性。在本研究计划中，我们将解决以下三个关键问题：1）MFG-E8如何抑制脓毒症中性粒细胞活化和浸润？2)CIRP如何引起败血症中血管EC活化和损伤？3)我们能否开发出一种针对嗜中性粒细胞-EC相互作用的抗菌策略？拟议的研究将为开发治疗脓毒症和脓毒性休克患者的创新疗法提供新的方向。